We will test the hypothesis that in heart failure and sudden death, heterogeneity and/or mismatch of pre- and post-synaptic regional cardiac SNS function are specific indicators of the extent and mechanisms of the diseases. Specifically, we hypothesize that the role of the cardiac SNS can be tested by in vivo quantitative measures of regional pre- and post-synaptic function. There is substantial evidence to support the concept that aberrations in cardiac SNS function contribute to and may be primarily responsible for the morbidity and mortality associated with sudden cardiac death (SCD) and congestive heart failure (CHF), two illnesses that are major public health problems. Aim 1 will demonstrate that pre- and post-synaptic cardiac function can be quantified over a wide range of neuronal function using physiologically realistic blood-tissue exchange models that are directly applicable to PET imaging studies. These experiments will be performed in isolated perfused hearts and in the in vivo canine hearts. Aim 2a is a pilot human study to test the hypothesis that quantitation of regional SNS dysfunction, using physiologically realistic models, will differentiate patients with recurrent SCD from those experiencing only a single episode and that the new analysis methods for both pre- and post-synaptic function are more definitive than are qualitative methods for evaluating SNS function. Aim 2b is a pilot human study to test the hypothesis that modulation of cardiac sympathetic function by central inhibition of the SNS in patients with CHF can be demonstrated by quantitation of regional pre-and post synaptic function. When related to changes in regional myocardial flow and metabolism, this quantitative approach provides a tool for understanding mechanisms of CHF and for evaluating new therapeutic strategies. Aim 1 will demonstrate that pre- and post-synaptic cardiac function can be quantified over a wide range of neuronal function using physiologically realistic blood-tissue exchange models that are directly applicable to PET imaging studies. These experiments will be performed in isolated perfused hearts and in vivo canine hearts. Aim 2a is a pilot human study to test the hypothesis that quantitation of regional SNS dysfunction, using physiologically realistic models, will differentiate patients with recurrent SCD from those experiencing only a single episode and that the new analysis methods for both pre- and post-synaptic function are more definitive than are qualitative methods for evaluating SNS function. Aim 2b is a pilot human study to test the hypothesis that modulation of cardiac sympathetic function by central inhibition of the SNS in patients with CHF can be demonstrated by quantitation of regional pre-and post synaptic function. When related to changes in regional myocardial flow and metabolism, this quantitative approach provides a tool for understanding mechanisms of CHF and for evaluating new therapeutic strategies.